Fifty Shades of Tolerance: Beyond a Binary Tolerant/Non-Tolerant Paradigm

It has long been considered that tolerance in a transplant recipient is a binary all-or-none state: either the graft is accepted without immunosuppression identifying the recipient as tolerant, or the recipient rejects the graft and is not tolerant. This tolerance paradigm, however, does not accurately reflect data emerging from animal models and patients and requires revision.

It is becoming appreciated that there may be different gradations in the quality of tolerance based on underlying cellular mechanisms of immunological tolerance, and that individuals may enhance their tolerance by strengthening or combining different cellular mechanisms. Furthermore, evidence suggests that even if tolerance is lost, the loss may be only temporary, and in some circumstances tolerance can be restored.

Shifting our focus from an all-or-nothing tolerance paradigm to one with many shades may help us better understand how tolerance operates, and how this state may be tracked and enhanced for better patient outcomes.